Efficacious treatments for cannabis use disorder (CUD) are critically needed yet there are currently no advanced development programs in the pharmaceutical industry focusing on cannabis treatment. This Strategic Alliance aims to develop a first-in-class medication ready for Phase II clinical testing for CUD, based on our recent discovery that pregnenolone (PREG) is an allosteric, signaling-specific, inhibitor of the type-1 cannabinoid receptor (CB1). CB1 agonists like ?9-tetrahydrocannabinol (THC) bind to the CB1 receptor activating a series of intracellular cascades. PREG, by binding to a distinct site on the CB1 receptor, selectively attenuates one of these intracellular effects (ERK1/2 activation), and in doing so, markedly reduces the somatic and behavioral effects of THC, including its self-administration. However, PREG is a poor medication (short half-life, poor bioavailability and conversion to downstream active steroids). We have developed a non-metabolized PREG derivative, AEF0117, that has a long half-life, is orally available, not converted into downstream active steroids, and that potently attenuates all of THC's effects in preclinical behavioral models (self-administration, food intake, memory impairment, tetrad effects). Importantly, AEF0117 produced none of the problems associated with orthosteric antagonists: precipitated withdrawal and mood-related side effects. The preclinical development of AEF0117 is almost complete and the IND for Phase I trials will be obtained shortly. Our objective is to leverage the significant financial investment of Aelis Farma to date to establish AEF0117 as a first-in-class treatment for CUD. The proposal has three components: A. Phase la trial: Tolerability and pharmacokinetics of escalating single and multiple oral doses of AEF0117 in healthy volunteers. B. Phase lb trial: Safety of AEF0117 (4 doses) in daily cannabis smokers, including assessment of precipitated withdrawal and effects on cannabis' positive subjective effects, food intake, sleep, cardiovascular effects, and cognitive task performance. C. Preclinical testing prior to Phase II: Complementary ADMET characterization of AEF0117 to ready the compound for a Phase II randomized clinical study. AEF0117 has been exceedingly safe in all preclinical studies, so we are confident that it will be successfully translated to human use. Yet there are clear entry and exit points along the development pathway, including contingencies if AEF0117 fails in Phase I testing. Given that the PI (Haney) has led the field in developing paradigms to screen candidate medications for CUD, her collaboration with a highly innovative preclinical investigator with experience in drug development (Piazza, INSERM), a biotech company (Aelis Farma, co-founded by Piazza) with substantial investment in AEF0117 development, as well as well-regarded regulatory consultants (Ready Clinical) has a high likelihood of success. We predict that this Strategic Alliance will allow us to rapidly advance and improve treatment for what will only be escalating rates of CUD, and will therefore have a high potential for immediate and far-reaching public health impact.